Recently, we described 9 different ribonucleoprotein (RNP) subsets within eukaryotic cells that often become targets for immune responses in patients with systemic lupus erythematosus (SLE) and other connective tissue diseases. Patient antibodies to these RNPs occurred selectively, and each antibody was exquisitely specific in its ability to immunoprecipitate individual RNP subsets. We hypothesize that these antibodies arise through a specific process of "autoimmunization". We now plan to extend our observations to include antibodies directed at components of deoxyribonucleoprotein (DNP). In combination with our earlier studies, this work will provide a comprehensive picture of the total spectrum of antibodies to nucleoproteins (both RNPs and DNPs) for comparison with clinical and other laboratory data. These studies will utilize newly developed assays based on immunoblotting (for analysis of protein antigens) and DNA-RNA hybridization (For detection of RNA components). We will identify all of the nucleoprotein determinants that participate frequently in the autoimmunity of SLE and compare the autoimmune responses of SLE with those of drug-induced SLE and Epstein-Barr virus infection. Once the precise targets are identified, we will characterize them structurally and biochemically and determine if they participate in the formation of circulating immune complexes. At a basic level, our studies will provide new information about chromatin structure. At a clincal level, they will determine whether nucleoprotein antigens are likely to initiate and propagate autoimmune responses in SLE. Identification of the mechanism(s) responsible for the induction of antinuclear antibodies (ANAs) is likely to provide an understanding of the etiology of SLE.